Iodinated esters

ABSTRACT

Water-insoluble iodinated esters of the formula (I) ##STR1## useful in X-ray and ultrasound imaging, are disclosed.

This application is a Division of application Ser. No. 08/315,502, filedSep. 30, 1994, now U.S. Pat. No. 5,416,223, which is a Division ofapplication Ser. No. 08/210,739, filed Mar. 21, 1994, now U.S. Pat. No.5,370,861, which is a Continuation of application Ser. No. 07/688,488,filed May 20, 1991, now abandoned.

The present invention relates to contrast agents for medical X-ray andultrasound imaging, and to their preparation and use.

It has been proposed to improve the detection of lesions in the liverand spleen by the use of contrast agents which accumulate in theseorgans. A number of substances have been suggested but there is no suchproduct on the market at the present time and each of the contrastagents so far proposed has some disadvantages.

Since the reticuloendothelial system of the liver and spleen is wellknown to trap particles by phagocytosis, contrast agents in particulateform are particularly well adapted for visualisation of these organs.Emulsions of iodinated oils have been proposed in this context,particularly iodinated ethyl esters of poppy seed oil. (Vermess, M., etal, Radiology, 137 (1980) 217). However, these substances have provedunduly toxic.

Another possibility is to use liposomes containing water solubleiodinated contrast agents. (Havron A. et al, Radiology, 140 (1981) 507].However, since only a limited amount of iodine can be incorporated ineach liposome, it is necessary to administer relatively large amounts oflipids in order to attain adequate contrast enhancement. This tends tocause emboli in the lung capillaries. Furthermore, liposomes have beenfound to be relatively unstable on storing (Shulkin, P. M., et al, J.Microencapsul., 1 (1984) 73).

Submicron thorium dioxide particles have been used for livervisualisation and have shown effective enhancement of contrast inclinical testing but their use has been discontinued because of theextremely lengthy retention of the particles in the liver. This, incombination with the inherent radioactivity of thorium, has led toserious adverse side effects, including neoplasm and fibrosis. (Thomas,S. F., Radiology, 78 (1962) 435).

It has also been proposed to use particles comprising the ethyl ester ofthe water soluble X-ray contrast agent, iodipamide (Violante, M. R., etal, Invest. Radiol., 2, (1984) 133). However, ethyl esters are notsufficiently metabolically labile and thus would be expected to beretained in the liver for a considerable period. Indeed, both this esterand an iodinated ethyl ester of poppy seed oil gave an increase in lipidvacuoles in the hepatocytes after intravenous administration. (Vermesset al, Radiology, 137 (1980) 217) and Violante M. R., Invest. Radiol., 2(1984) 133). Such morphological changes indicate an adverse effect onthe hepatocytes.

Acyloxyalkyl esters of carboxylic acids containing a tri-iodophenylgroup are known as contrast agents from GB-A-1363847, U.S. Pat. No.4,018,783 and GB-A2157283. In U.S. Pat. No. 4,018,783 the compounds areprimarily suggested for X-ray imaging of the bronchial system, while inGB-A-2157283 the most preferred use is in a liposome carrier inlymphography

We have now found that particularly advantageous contrast agents for thevisualisation of the liver and spleen comprise particulate lipophiliciodine-containing carbonate esters which are metabolically labile toform water-soluble substances which are substantially non-toxic and arenot retained in the target organs.

According to the present invention we provide metabolically labilewater-insoluble iodinated esters of the formula (I): ##STR2## in which

R¹ is a substituted or unsubstituted C₁₋₂₀ aliphatic, C₇₋₂₀ -araliphaticor C₆₋₂₀ aryl group or a C₁₋₂₀ heterocyclic group having one or morehetero atoms selected from O, S and N;

R² is hydrogen or a substituted or unsubstituted C₁₋₆ aliphatic group,C₆₋₁₀ aryl group or C₇₋₂₀ araliphatic group;

R³ is a group as defined above for R¹, which may be the same as ordifferent from R¹,

or R² and R³ and together represent a substituted or unsubstituted C₁₋₄alkylene group,

the molecule containing at least one iodine atom and being metabolisableto products which are soluble in body fluids and are physiologicallyacceptable.

Where the group R³ is not joined to R² the metabolic products will be R¹COOH, R² CHO, R³ OH and carbon dioxide. Where R³ and R² together form analkylene group, the products will be R¹ COOH and HO(R³.R²)CHO and carbondioxide

Aliphatic groups may be straight or branched, saturated or unsaturatedand include, for example, alkyl and alkenyl groups e.g. methyl, ethyl,isopropyl, butyl or allyl groups. Araliphatic groups includemonocarbocyclic aryl-alkyl groups; for example benzyl groups. Arylgroups include mono- or bi-cyclic aryl groups, for example phenyl, tolylor naphthyl groups. Heterocyclic groups include 5 or 6- memberedheterocyclic groups preferably having one heteroatom, for example furyl,thienyl or pyridyl groups.

Possible substituents in the above hydrocarbon groups R¹, R² and R³include hydroxyl etherified hydroxyl, esterified hydroxyl, etherifiedthiol, N-alkylamino, N-C₁₋₆ -acylamino, N-C₁₋₆ -acyl-N-C₁₋₆ alkylamino,carbamoyl and N-C₁₋₆ alkylcarbamoyl groups and halogen atoms. It shouldbe noted that aromatic rings such as phenyl may carry C₁₋₆ alkyl groups,as in the tolyl group. Substituents may be present in combination andthus, for example, N-acyl and N-alkyl groups may carry hydroxy oretherified or esterified hydroxyl groups.

Etherified hydroxyl groups include C₁₋₅ alkoxy groups such as methoxygroups. Adjacent hydroxy groups may be etherified with a single bridginggroup, such as an acetonide group. Esterified hydroxyl groups includeC₁₋₆ acyloxy groups such as acetoxy groups.

Halogen atoms include fluorine, chlorine, bromine and iodine. More thanone halogen atom may be present in any particular group, as in thetrifluoromethyl group. It is particularly preferred that the molecule asa whole carries several iodine atoms, for example at least three.

It is particularly preferred that at least one of the groups R¹ and R³contains an iodinated phenyl group, preferably a triiodophenyl group.Such a group may be selected from the very wide range of such groupspresent in commercial carboxylic acid or non-ionic amide X-ray contrastagents. Such groups include 2,4,6-triiodophenyl groups having at the 3-and/or 5-positions groups selected from carbamoyl, N-alkylcarbamoyl orN-hydroxyalkylcarbamoyl, acylamino, N-alkyl-acylamino andacylaminomethyl groups. In such groupings, acyl groups will commonly beacetyl groups and N-alkylacylamino groups will commonly beN-methylacetamino groups. N-hydroxyalkylcarbamoyl groups will commonlycomprise 1,3 or 2,3-dihydroxypropyl groups as the hydroxyalkyl moiety.In the group R¹ the triiodophenyl group will preferably be linkeddirectly to a carbonyl group, i.e. the compound of Formula (I) will bean ester of a triiodobenzoic acid derivative, for example an X-raycontrast acid such as metrizoic acid, diatrizoic acid, iothalamic acidand ioxaglic acid. In the group R³, however the triiodophenyl group maybe linked directly to the oxygen atom (the compound then contains asubstituted triiodophenoxy group) or via a bridging group as in thehydroxyalkylamino, N-hydroxyalkylcarbamoyl or hydroxyacylamino groupspresent in such non-ionic X-ray contrast agents as iohexol, iopentol,iopamidol, iopromide and metrizamide. Where such non-ionic contrastagents have multiple hydroxyl groups, the group R¹ CO.O.CHR².O.CO.O--may be attached at more than one position in the group R³.

It is important that the contrast agent according to the invention issubstantially water-insoluble and thus, when administered in particulateform, will be entrapped by the liver or spleen. It is possible forrelatively hydrophilic groups, such as hydroxyl, to be present providedthe remainder of the molecule is sufficiently lipophilic to ensureminimal overall water-solubility. However, after metabolic enzymolysis,it is important that the metabolic products have sufficientwater-solubility at physiological pH to be excreted from the targetorgans. They should also themselves be physiologically acceptable.

We have found that particulate compounds according to the invention onintravenous administration appear to be captured by thereticuloendothelial system of the liver and spleen, the resultingaccumulation of particles greatly assisting the imaging of these organs.On the other hand, the phagocytosing cells of the liver (Kupffer cells)contain lysosomes which possess a broad spectrum of hydrolyric enzymesincluding a number of esterases. Thus, once the particles arephagocytised, they enter the lysosomes and are converted intowater-soluble products which are subsequently excreted. The relativerapidity of the conversion of the compounds into water-soluble productssignificantly decreases the risk of toxic reactions.

As compared with liposomes, the particles of solid contrast agentaccording to the invention have a very much higher iodine content. Thus,to achieve a desired level of contrast, as provided by a particularamount of iodine, a far smaller amount of material has to be used andthe risk of producing lung emboli is greatly reduced. Furthermore, theparticulate material according to the invention, which is commonlycrystalline, is generally much more stable to storage than thepreviously proposed liposomes.

The compounds of the invention, due to their iodine content, provideexcellent X-ray image enhancement. Due to the presence of the relativelyheavy iodine atoms, the particles reflect ultrasound and can also beused in enhancement of ultrasound images.

The particulate compounds according to the invention are rapidlyaccumulated in the liver and spleen and are then retained in the organs,allowing imaging to take place on a more convenient timescale than withknown non-ionic contrast agents where any retention in the liver istransient.

Thus when maximum liver-iodine concentration is reached, a concentration"plateau" is achieved which allows imaging to be carried out over a longperiod. When the elimination of the contrast agent from the liverbegins, it proceeds very quickly so that the contrast agent iseliminated from the body after a short period.

This profile of liver uptake and excretion is particularly beneficialand represents a significant advantage over the prior art.

The particulate compounds of the invention also have low toxicity, forexample about 4 times lower than the toxicity of correspondingparticulate ester derivatives in which R³ O.CO is replaced by R³ CO.

The invention also provides injectable contrast media comprising acompound according to the invention in particulate form in suspension ina liquid for injection.

The mean particle size of the contrast agent will, in general, be withinthe range 0.002 to 7 microns, preferably 0.01 to 3 microns.

The injectable liquid may be any sterile physiologically acceptableliquid such as physiological saline which may usefully contain aphysiologically acceptable stabilising agent such as bovine serumalbumen, human serum albumin, propylene glycol, gelatin,polyvinylpyrrolidone (for example having a molecular weight about 30,000daltons), or a polysorbate (for example Polysorbate 80) or combinationsof two or more of these stabilising agents.

The contrast media may be used in the enhancement of X-ray andultrasound images of the liver and/or spleen of a human or non-humananimal subject, in which method they will be administeredintravascularly, normally intravenously, prior to imaging.

The compounds according to the invention may be prepared in anyconvenient way. In general, the compounds will be formed byesterification of an acid of the formula R¹ COOH or a functionalderivative thereof with a compound of the formula X--CHR².O.CO.OR³,where X is a leaving group such as a halogen atom or a mesyloxy ortosyloxy group. Where X represents a leaving group, the functionalderivative of the acid of formula R¹ COOH will normally be a salt suchas the potassium salt. Such a reaction will normally be carried out insolution, for example in a polar solvent such as dimethylformamide.

The compound X--CHR².O.CO.OR³ where X is halogen may in turn be preparedfrom R² CHO and a compound of formula X¹.CO.OR³ wherein X¹ is halogenatom in the presence of a base such as pyridine.

The intermediates X--CHR².O.CO.OR³ may also be made by coupling acompound of formula X--CHR² --O.CO.Hal with an alcohol of formula R³ OH,Hal being a halogen atom. Where the group R³ contains multiple hydroxylgroups as in iohexol, it may be desirable to protect certain of thesewith, for example, acetonide groupings, in order to ensure reaction at asingle hydroxyl group. Such acetonide groups may if desired remain inthe final compound according to the invention.

The particulate form of the contrast agent according to the inventionmay advantageously be prepared by precipitation from solution in awater-miscible solvent such as ethanol by admixture with water, whichmay conveniently contain a stabilising agent such as bovine serumalbumin, human serum albumin, gelatin, polyvinylpyrrolidone, propyleneglycol or a polysorbate, with vigorous agitation, e.g. using ultrasound.In this way, it is possible to obtain particles of mean diameter of theorder of 1.0 microns. Mechanical crushing or spray drying, for exampleto an appropriate particle size is also suitable. The particles may bedispersed in the liquid for injection referred to above.

The following Examples are given by way of illustration only. Seronormis a test serum available from Nycomed AS, Oslo, Norway.

EXAMPLE 1 1-(Ethyloxvcarbonyloxy)ethyl5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate

1-Chloroethyl ethyl carbonate (10.00 g, 66.0 mmol) was added dropwiseduring 1.5 hour at room temperature to a solution of potassium5-(N-acetylamino)3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate(40.00 g, 60.0 mmol) and sodium iodide (0.89 g, 6.0 mmol) in drydimethylformamide (200 ml). After stirring at 50° C. for 24 hours thesolvent was removed at reduced pressure. The residue was dissolved inchloroform (120 ml) and washed four times with a saturated sodiumhydrogen carbonate solution and twice with water. After drying withmagnesium sulfate, treatment with activated charcoal and filtration, thetitle compound was crystallised by concentrating the solution at reducedpressure. Yield: (79%). Purity by HPLC: 99%. ¹ H-NMR (DMSO-d₆):delta=1.25 (t, J=7 Hz, CH₃); 1.64 (d, J=6 Hz, CH₃); 1.67 (s,N(Me)COCH₃); 2.05(s, NCOCH₃); 2.96 (s, NCH₃); 4.21 (q, J=7 Hz, CH₂);6.97 (q, J=6 Hz, CH); 10.10 ppm (s, NH).

EXAMPLE 2 1-(Ethyloxycarbonyloxy)ethyl5-(N-acetylamino)-3-(N-methylaminocarbonyl)-2,4,6-triiodobenzenecarboxylate

1-Chloroethyl ethyl carbonate (1.67 g, 11.0 mmol) was added dropwise atroom temperature to a solution of potassium5-(N-acetylamino)-3-(N-methylaminocarbonyl)-2,4,6-triiodobenzenecarboxylate(6.52 g, 10.0 mmol) and sodium iodide (150 Mg, 1.0 mmol) in dry DMF (50ml). After stirring at 50° C. for 24 hours the solvent was removed atreduced pressure. The residue was dissolved in chloroform and washedfour times with a saturated sodium hydrogen carbonate solution and twicewith water. After drying with magnesium sulfate and filtration, thesolvent was removed at reduced pressure to give the title compound.Yield: (2.2 g, 38%). Purity by HPLC: 98%. ¹ H-NMR (DMSO-d₆ ): delta=1.24(t, J=7 Hz, CH₃); 1.63 (d, J=6 Hz, CH₃); 2.03 (s, CH₃ CO); 2.75 (d, J=3Hz, NCH₃); 4.21 (q, J=7 Hz, CH₂): 6.93 (q, J=6 Hz, CH); 8.4-8.7 (m,NHMe); 10.03 ppm (s, NHAc).

EXAMPLE 3 1-(Ethyloxycarbonyloxy)ethyl3-(alpha-(3-(N-acetyl-N-methylamino)-5-(methylaminocarbonyl)-2,4,6-triiodobenzoylamino)-acetylamino)-5-(N-(2-hydroxyethyl)aminocarbonyl)-2,4,6-triiodo-benzenecarboxylate

1-Chloroethyl ethyl carbonate (0.84 g, 5.5 mmol) was added dropwise atroom temperature to a solution of cesium3-(alpha-(3-(N-acetyl-N-methylamino)-5-(methylaminocarbonyl)-2,4,6-triiodobenzoylamino)-acetylamino)-5-(N-2-hydroxyethyl)aminocarbonyl)-2,4,6-triiodo-benzenecarboxylate(7.00 g, 5.0 mmol) and sodium iodide (75 Mg, 0.5 mmol) in dry DMF (25ml). After stirring at 50° C. for 24 hours the solvent was removed atreduced pressure. The residue was triturated, washed and filteredrepeatedly, first with CHCl₃ and finally with H₂ O, to give the titlecompound. Yield: (5.7 g, 82%). Both ¹ H-- and ¹³ C--NMR are similar forthe title compound and the starting material (as free carboxylic acid)except for the carboxylic acid itself which is esterified in the titlecompound. ¹ H-NMR (DMSO-d₆) of the 1-ethyloxycarbonyloxyethyl group ofthe title compound is: delta=1.24 (t, J=7 Hz, CH₃); 1.63 (d, J=6 Hz,CH₃); 4.21 (q, J=7 Hz, CH₂); 6.94 ppm (q, J=6 Hz, CH). These chemicalshifts are in accordance with the title compounds of Examples 1 and 2,and not with 1-chloroethyl ethyl carbonate which is the startingmaterial (delta=1.24 (t, J=7 Hz, CH₃); 1.76 (d, J=6 Hz, CH₃); 4.21 (q,J=7 Hz, CH₂) 6.51 ppm (q, J=6 Hz, CH)).

EXAMPLE 4 1,3-Dioxolan-2-one-4-yl5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate

4-Chloro-1,3-dioxolan-2-one (1.35 g, 11 mmol) was added at roomtemperature to a solution of potassium5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate(6.66 g, 10 mmol) and sodium iodide (0.15 g, 1 mmol) in dry DMF (50 ml).After stirring at 50° C. for 6 hours and at room temperature for 4 daysthe solvent was removed at reduced pressure. The residue was dissolvedin chloroform (100 ml) and washed four times with a saturated sodiumhydrogen carbonate solution and finally twice with water. Aftertreatment with magnesium sulfate the solution was finally evaporated todryness. Yield: 5.6 g. Purity by HPLC: 93%. ¹ H-NMR (DMSO-d₆):delta=1.67 (N (CH₃)COCH₃); 2.05(NCOCH₃); 2.96(NCH₃); 4.7; 4.9(CH₂);7.02(CH); 10.14 ppm(NH).

EXAMPLE 5 1-(Phenyloxycarbonyloxy)ethyl5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate

1-Chloroethyl phenyl carbonate (prepared according to Synthesis 1986,627) (2.21 g, 11 mmol) was added at room temperature to a solution ofpotassium5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate(6.66 g, 10 mmol) and potassium iodide (0.17 g, 1 mmol) in dry DMF.After stirring at 50° C. for 6 hours and at room temperature for 4 daysthe solvent was removed at reduced pressure. The residue was suspendedin chloroform (100 ml) and washed four times with a saturated sodiumhydrogen carbonate solution and twice with water. After drying withmagnesium sulfate the solution was evaporated to dryness. Yield: 7.3 g.Purity by HPLC: 98%. ¹ H-NMR (DMSO-d₆): delta=1.68 (N(CH₃)COCH₃); 1.74(CHCH₃); 2.05 (NCOCH₃); 2.97 (NCH₃); 7.05 (CH); 7.25-7.52 (arom.); 10.14ppm (NH).

EXAMPLE 6 1-(Benzyloxycarbonyloxy)ethyl5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate

1-Chloroethyl benzyl carbonate (prepared according to Synthesis 1986,627), (2.36 g, 11.0 mmol) was added at room temperature to a solution ofpotassium5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate(6.66 g, 20 mmol) and sodium iodide (0.15 g, 1 mmol) in dry DMF (50 ml).After stirring at 50° C. for 7 hours and at room temperature for 7 daysthe solvent was removed at reduced pressure. The residue was dissolvedin chloroform (100 ml) and washed four times with a saturated sodiumhydrogen carbonate solution and twice with water. After treatment withmagnesium sulfate the solution was evaporated to dryness. Yield: 6.8 g.Purity by HPLC: 97% ¹ H-NMR(DMSO-d₆): delta=1.64 (CHCH₃);1.66(N(CH₃)COCH₃); 2.05 (NCOCH₃); 5.23 (CH₂); 7.00 (CH); 7.30-7.45(arom.); 10.12 ppm (NH).

EXAMPLE 7 1-(Thenyloxycarbonyloxy)ethyl5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylatei) 1-Chloroethyl Thenyl Carbonate

1-Chloroethyl chloroformate (28.6 g, 0.2 mol) and2-hydroxymethyl-thiophene (20.6 g, 0.18 mol) were dissolved inchloroform (220 ml) at 0° C. Pyridine (15.8 g, 0.2 mol) was addeddropwise during 35 minutes maintaining the temperature below 10° C.After stirring at room temperature for 24 hours the precipitate wasfiltered off. The organic phase was washed three times with 1 normalhydrochloric acid, once with a saturated sodium hydrogen carbonatesolution and finally twice with water. The organic solution was driedwith magnesium sulfate and the solvent was removed at reduced pressure.The residue was distilled in vacuo. Yield: 36.5 g. ¹ H-NMR (DMSO-d₆):delta=1.76 (CH₃); 5.41 (CH₂); 6.53 (CHCH₃); 7.04, 7.25; 7.59 ppm(thiophene).

ii) 1-(Thenyloxycarbonyloxy)ethyl5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate

1-Chloroethyl thenyl carbonate (2.43 g, 11 mmol) was added at roomtemperature to a solution of potassium5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate(6.66 g, 10 mmol) and potassium iodide (0.17 g, 1 mmol) in dry DMF.After stirring at 50° C. for 5 hours and at room temperature for 4 daysthe solvent was removed at reduced pressure. The residue was suspendedin chloroform (100 ml) and washed three times with a saturated sodiumhydrogen carbonate solution and finally twice with water. After dryingwith magnesium sulfate the solution was evaporated to dryness. Yield:7.9 g. Purity by HPLC: 88%. ¹ H-NMR (DMSO-d₆): delta=1.64 (CHCH₃); 1.65(N(CH₃)COCH₃); 2.05 (NCOCH₃); 2.95 (NCH₃); 5.41 (CH₂); 7.00 (CHCH₃);7.05; 7.25; 7.61 (thiophene); 10.11 ppm (NH).

EXAMPLE 8 1-(2-Methoxyethyloxycarbonyloxy)ethyl5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylatei) 1-Chloroethyl 2-methoxyethane carbonate

1-Chloroethyl chloroformate (28.6 g, 0.2 mol) and 2-methoxyethanol (13.7g, 0.18 mol) were dissolved in chloroform (220 ml) at 0° C. Pyridine(15.8 g, 0.2 mol) was added dropwise during 45 minutes maintaining thetemperature below 12° C. After stirring at room temperature for 2 hoursthe mixture was washed three times with 1 normal hydrochloric acid, oncewith a saturated sodium hydrogen carbonate solution and finally twicewith water. The organic phase was dried with magnesium sulfate and thesolvent was removed at reduced pressure. The residue was distilled invacuo. Yield: 75%. ¹ H-NMR: delta=1.76 (CHCH₃); 3.27 (OCH₃); 3.55 (CH₂OCH₃); 4.27 (COOCH₂); 6.51 (CH).

ii) 1-(2-Methoxyethyloxycarbonyloxy)ethyl5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate

1-Chloroethyl 2-methoxyethane carbonate (2.0 g, 11 mmol) was added atroom temperature to a solution of potassium5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate(6.66 g, 10 mmol) and potassium iodide (0.17 g, 1 mmol) in dry DMF.After stirring at 50° C. for 4 hours and at room temperature for 3 daysthe solvent was removed at reduced pressure. The residue was suspendedin chloroform (100 ml) and washed three times with a saturated sodiumhydrogen carbonate solution and finally twice with water. After dryingwith magnesium sulfate the solution was evaporated to dryness. Yield:7.1 g. Purity by HPLC: 79%. ¹ H-NMR (DMSO-d₆): delta=1.65 (CHCH₃); 1.66(N(CH₃)COCH₃); 2.05 (NCOCH₃); 2.96 (NCH₃); 3.26 (OCH₃); 3.55 (CH₂ OCH₃);4.29 (COOCH₂); 6.98 (CH); 10.12 ppm (NH). FAB-MS: M+1=775.

EXAMPLE 91-(2-[N-(3,5-bis-((2,2-dimethyl-1,3-dioxolan-4-yl)-methylaminocarbonyl)-2,4,6-triiodophenyl)-acetylamino]ethyloxycarbonyloxy)ethyl5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate(i) 1-Chloroethyl2-(N-(3,5-bis-((2,2-dimethyl-1,3-dioxolan-4-yl)-methylaminocarbonyl)-2,4,6-triiodophenyl)-acetylamino)ethylCarbonate

1-Chloroethyl chloroformate (0.77 g, 5.5 mmol) and5-(N-acetyl-N-(2-hydroxyethyl)amino)-N,N'-bis((2,2-dimethyl-1,3-dioxolan-4-yl)-methyl)2,4,6-triiodo-1,3-benzenedicarboxamide(4.36 g, 5 mmol) were dissolved in dichloromethane (10 ml) at 0° C.Pyridine (4.35 mg, 5.5 mmol) was added during 45 min. After stirring at0° C. for one hour 1-chloroethyl chloroformate (0.77 g, 5.5 mmol) andpyridine (4.35 mg, 5 .5 mmol) were added once more. After three days atroom temperature the mixture was washed four times with 0.1 normalhydrochloric acid, twice with a saturated sodium hydrogen carbonatesolution and finally once with water. The organic phase was dried withmagnesium sulfate and the solvent was evaporated under reduced pressure.Yield 3.8 g.

ii)1-(2-[N-(3,5-bis-((2,2-dimethyl-1,3-dioxolan-4-yl)-methylaminocarbonyl)-2,4,6-triiodophenyl)-acetylamino)]ethyloxycarbonyloxy)ethyl5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate

1-Chloroethyl2-(N-(3,5-bis-((2,2-dimethyl-1,3-dioxolan-4-yl)-methylaminocarbonyl)-2,4,6-triiodophenyl)-acetylamino)ethylcarbonate (3.1 g, 3.3 mmol) was added at room temperature to a solutionof potassium5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate(2.00 g, 3 mmol) and potassium iodide (50 mg, 0.3 mmol) in dry DMF.After stirring at 50° C. for 18 hours and at room temperature for oneday the solvent was removed at reduced pressure. The residue wassuspended in chloroform (50 ml) and DMF (5 ml) and washed twice with asodium hydrogen carbonate solution and twice with water. After treatmentof the organic phase with magnesium sulfate and charcoal the solutionwas evaporated to dryness. Yield: 2.65 g. FAB-MS: M+1=1528.

EXAMPLE 101-(2-(N-(3,5-bis((2,3-dihydroxypropyl)-aminocarbonyl)-2,4,6-triiodophenyl)-acetylamino)-ethyloxycarbonyloxy)ethyl5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate

1-(2-[N-(3,5-bis((2,2-dimethyl-1,3-dioxolan-4-yl)-methylaminocarbonyl)-2,4,6-triiodophenyl)-acetylamino]ethyloxycarbonyloxy)ethyl5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate(0.5 g, 0.3 mmol) was dissolved in DMF (3.5 ml) and water (1.5 ml). 1Nhydrochloric acid (0.6 ml, 0.6 mmol) was added at room temperature.After stirring at 50° C. for 2 hours the solution was evaporated todryness. Yield: 0.4 g. FAB/MS: 1490 (M+H⁺).

EXAMPLE 11 1-(Ethyloxycarbonyloxy)ethyl3,5-di(acetylamino)-2,4,6-triiodobenzenecarboxylate

1-Chloroethyl ethyl carbonate (1.68 g, 11.0 mmol) was added at roomtemperature to a solution of potassium3,5-di(acetylamino)-2,4,6-triiodobenzenecarboxylate (6.52 g, 10.0 mmol)and sodium iodide (0.30 g, 2.0 mmol) in dry DMF (100 ml). After stirringat 60° C. for 2 hours and at 40° C. for 65 hours the solvent was removedat reduced pressure. The residue was suspended in chloroform (100 ml)and washed four times with a saturated sodium hydrogen carbonatesolution and finally twice with water. After drying with magnesiumsulfate the solution was evaporated to dryness. Yield: 2.45 g Purity byHPLC: 98.5% ¹ H-NMR(DMSO-d₆): delta=1.24(CH₂ CH₃); 1.63(CHCH₃);2.02(COCH₃); 4.20(CH₂ CH₃); 6.93(CHCH₃); 10.03 ppm (NH). FAB/MS: 731(M+H⁺)

EXAMPLE 12 Phenyloxycarbonyloxymethyl5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate(i) Chloromethyl Phenyl Carbonate

Phenyl chloroformate (9.0 g, 57.5 mmol) was dissolved in1,2-dichloroethane (50 ml) and pyridine (0.22 g, 2.8 mmol) was addeddropwise to the stirred solution. In another reactor, paraformaldehyde(7.0 g, 233.1 mmol) was heated with a heat gun to generate the gaseousmonomer. The formaldehyde gas was bubbled into the first reactor througha tube with the outlet below the surface of the liquid. Stirred at 65°C. for 3 hours. Washed three times with water, dried (MgSO₄) andconcentrated. Distillation (Bp. 64°-67° C. 5×10⁻⁴ mbar) yielded 2.7 gproduct. The product was further purified by flash chromatography(Silikagel 60, petroleum ether/ethyl acetate 95: 5). Yield: 2.1 g. ¹H-NMR (CDCl₃): delta=5.78 (CH₂); 7.18-7.41 ppm (phenyl).

ii) Phenyloxycarbonyloxymethyl5-N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate

Chloromethyl phenyl carbonate (0.50 g, 2.7 mmol) was added at roomtemperature to a solution of potassium5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate(1.62 g, 2.4 mmol) and sodium iodide (0.038 g, 0.25 mmol) in dry DMF (15ml). After stirring at 50° C. for 5 hours and at room temperature for 18hours the solvent was removed at reduced pressure. The residue wassuspended in chloroform (25 ml) and washed four times with a saturatedsodium hydrogen carbonate solution and finally twice with water. Afterdrying with magnesium sulfate the solution was evaporated to dryness.Yield: 0.67 g Purity by HPLC: 99.2% ¹ H-NMR(DMSO-d₆): delta=1.68 (NCH₃COCH₃); 2.06 (NHCOCH₃); 2.97 (NCH₃); 6.08 (CH₂); 7.28-7.49 (phenyl);10.14. ppm (NH). FAB/MS: 779 ((M+H)⁺).

EXAMPLE 13 1-(Phenyloxycarbonyloxy)-3-phenylpropyl5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylatei) 1-Chloro-3-phenylpropyl phenyl carbonate

Phenyl chloroformate (0.80 g, 5.1 mmol) and 3-phenyl-propionaldehyde(0.96 g, 7.2 mmol) were dissolved in 1,2-dichloroethane (5 ml) andpyridine (0.020 g, 0.25 mmol) was added dropwise to the stirredsolution. Stirred at 80° C. for 2 days. Washed with water (10 ml), dried(MgSO₄) and concentrated. Purified by flash chromatography (Silikagel60, petroleum ether/ethyl acetate 95:5). Yield: 0.45 g ¹ H-NMR (CDCl₃):delta=2.43 (CH₂ CH); 2.87 (CH₂ CH₂ CH); 6.34 (CH); 7.19-7.41 ppm(phenyl).

ii) 1-(Phenyloxycarbonyloxy)-3-phenylpropyl5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate

1-Chloro-3-phenylpropyl phenyl carbonate (0.30 g, 1.03 mmol) was addedat room temperature to a solution of potassium5-(N-acetylamino)-3-(N-acetyl-N-methyl-amino)-2,4,6-triiodobenzenecarboxylate(0.62 g, 0.93 mmol) and sodium iodide (0.014 g, 0.093 mmol) in dry DMF(5 ml). After stirring at 50° C. for 5 hours and at room temperature for2 days the solvent was removed at reduced pressure. The residue wassuspended in chloroform (15 ml) and washed four times with a saturatedsodium hydrogen carbonate solution and finally twice with water. Afterdrying with magnesium sulfate the solution was evaporated to dryness.Yield: 0.26 g. Purity by HPLC: 94.4% ¹ H-NMR (DMSO-d₆): delta=1.68 (NCH₃COCH₃); 2.06 (NHCOCH₃); 2.38 (CH₂ CH); 2.83 (CH₂ CH₂ CH); 2.98 (NCH₃);7.02 (CH); 7.19-7.52 (phenyl); 10.15 ppm (NH). FAB/MS: 883 ((M+H⁺).

EXAMPLE 14 1-(Phenyloxycarbonyloxy)pentyl5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylatei) 1-Chloropentyl Phenyl Carbonate

Phenyl chloroformate (2.0 g, 12.8 mmol) and n-valeraldehyde (1.3 g, 15.1mmol) were dissolved in 1,2-dichloroethane (10 ml) and pyridine (0.06 g,0.76 mmol) was added dropwise to the stirred solution. Stirred at 80° C.for 1 day. Washed with water (10 ml), dried (MgSO₄) and concentrated.Purified by flash chromatography (Silikagel 60, petroleum ether/ethylacetate 95:5). Yield: 0.26 g GC/MS: 242.0 (M⁺).

ii) 1-(Phenyloxycarbonyloxy)pentyl5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate

1-Chloropentyl phenyl carbonate (0.14 g, 0.58 mmol) was added at roomtemperature to a solution of potassium5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate(0.35 g, 0.53 mmol) and sodium iodide (0.008 g, 0.053 mmol) in dry DMF(3 ml). After stirring at 50° C. for 5 hours and at room temperature for2 days the solvent was removed at reduced pressure. The residue wassuspended in chloroform (15 ml) and washed four times with a saturatedsodium hydrogen carbonate solution and finally twice with water. Afterdrying with magnesium sulfate the solution was evaporated to drynes.Yield: 0.04 g. Purity by HPLC: 94.8% ¹ H-NMR (DMSO-d₆): delta=0.92(CH₃CH₂); 1.31-1.55 (CH₃ CH₂ CH₂); 1.68 (NCH₃ COCHhd 3); 2.04 (CH₂ CH); 2.05 (NHCOCH₃); 2.97 (NCH₃); 6.95 (CH); 7.27-7.49 (phenyl); 10.13 ppm(NH). FAB/MS: 835 ((M+H)⁺).

EXAMPLE 15 1-(Phenyloxycarbonyloxy)-1-phenylmethyl5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylatei) 1-Chloro-1-phenylmethyl Phenyl Carbonate

Phenyl chloroformate (3.0 g, 19.2 mmol) and benzaldehyde (2.4 g, 23.0mmol) were dissolved in 1,2-dichloroethane (15 ml) and pyridine (0.09 g,1.14 mmol) was added dropwise to the stirred solution. Stirred at 80° C.for two days and at 100° C. for one day. Washed with water (25 ml), theaqueous phase was back-extracted with dichloromethane (25 ml). Thecombined organic phases were dried (MgSO₄) and concentrated. Purified byflash chromatography (Silikagel 60, petroleum ether/ethyl acetate 95 5).Yield: 1.5 g. ¹ H-NMR (CDCl₃): delta=7.34 (CH); 7.20-7.61 ppm (phenyl).GC/MS: 262.1 (M⁺).

ii) 1-(Phenyloxycarbonyloxy)-1-phenylmethyl5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate

1-Chloro-1-phenylmethyl phenyl carbonate (0.63 g, 2.4 mmol) was added atroom temperature to a solution of potassium5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate(1.44 g, 2.2 mmol) and sodium iodide (0.034 g, 0.23 mmol) in dry DMF (12ml). After stirring at 60° C. for 2 hours and at room temperature for 18hours the solvent was removed at reduced pressure. The residue wassuspended in chloroform (20 ml) and washed four times with a saturatedsodium hydrogen carbonate solution and finally twice with water. Afterdrying with magnesium sulfate the solution was evaporated to dryness.Yield: 0.90 g. Purity by HPLC: 96.6% ¹ H-NMR(DMSO-d₆): delta=1.67 (NCH₃COCH₃); 2.05 (NHCOCH₃); 2.96 (NCH₃); 7.29-7.54 (phenyl); 7.71 (CH);10.13 ppm (NH). FAB/MS: 854 (M⁺).

EXAMPLE 16 1-(Hexyloxycarbonyloxy)ethyl5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylatei) 1-Chloroethyl Hexyl Carbonate

1-Chloroethyl chloroformate (10.0 g, 69.9 mmol) and 1-hexanol (6.5 g,63.6 mmol) were dissolved in chloroform (80 ml) at 0° C. Pyridine (5.5g, 69.5 mmol) was added dropwise during 17 minutes maintaining thetemperature below 10° C. After stirring at room temperature for 20 hoursthe organic phase was washed three times with 1 normal hydrochloricacid, once with a saturated sodium hydrogen carbonate solution andfinally twice with water. The organic solution was dried with magnesiumsulfate and the solvent was removed at reduced pressure. The residue(11.6 g) was distilled in vacuo (Bp. 61°-72° C., 3×10⁻³ mbar). Yield:9.0 g. ¹ H-NMR (CDCl₃): delta=0.89 (CH₂ CH₃); 1.28-1.40 (CH₂ CH₂ CH×₂CH₃); 1.69 (OCH₂ CH₂); 1.83 (CH₃ CH); 4.20 (OCH₂); 6.43 ppm (CH).

ii) 1-(Hexyloxycarbonyloxy)ethyl5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate

1-Chloroethyl hexyl carbonate (0.47 g, 2.3 mmol) was added at roomtemperature to a solution of potassium5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate(1.51 g, 2.3 mmol) and sodium iodide (0.036 g, 0.24 mmol) in dry DMF (12ml). After stirring at 60° C. for 3 hours and at room temperature for 18hours the solvent was removed at reduced pressure. The residue wassuspended in chloroform (20 ml) and washed three times with a saturatedsodium hydrogen carbonate solution and finally twice with water. Afterdrying with magnesium sulfate the solution was evaporated to dryness.Yield: 0.88 g, Purity by HPLC: 95.2% ¹ H-NMR (DMSO-d₆); delta=0.86 (CH₂CH₃); 1.22-1.36 (CH₂ CH₂ CH₂ CH₃); 1.62 (OCH₂ CH₂); 1.64 (CHCH₃); 1.66(NCH₃ COCH₃); 2.04 (NHCOCH₃); 2.95 (NCH₃); 4.16 (OCH₂); 6.96 (CH); 10.11ppm (NH). FAB/MS: 801 ((M+H)⁺).

Particle Preparation 1

Bovine serum albumin, BSA, (0.75 g) was dissolved in distilled water(25.0 ml) and filtered through a membrane filter with pore size 0.45micron. A filtered solution (0.22 micron) of the product of Example 1(0.2 g) in 96% ethanol (5.0 ml) was slowly added to the BSA solutionunder vigorous stirring over a prolonged period of time. Themicroparticles formed were centrifuged and washed repeatedly. The sizeand size-distribution of the particles were analysed by CoulterMultisizer and light- and electron microscopy. The mean diameter was 2.0microns, which was also the diameter of the main fraction.

Particle Preparation 2

Bovine serum albumin, BSA, (0.75 g) was dissolved in distilled water(25.0 ml) and filtered through a membrane filter with pore size 0.45micron. A filtered solution (0.22 micron) of the product of Example 1(0.2 g) in 96% ethanol (5.0 ml) was slowly added to the BSA solutionunder vigorous ultrasonic stirring over a prolonged period of time. Themicroparticles formed were centrifuged and washed repeatedly. The sizeand size-distribution of the particles were analysed by CoulterMultisizer and light microscopy. The mean diameter was 2.0 microns,which was also the diameter of the main fraction.

Particle Preparation 3

A solution containing 2% polysorbat 80 (Tween 80) in distilled water wasprepared (25.0 ml) and filtered through a membrane filter (0.45 micron).A filtered solution (0.22 micron) of the product of Example 1 (0.2 g) in96% ethanol (5.0 ml) was slowly added to the Tween 80 solution undervigorous stirring. The microparticles formed were centrifuged and washedrepeatedly before reconstitution in sterile phosphate buffered saline(1.8 ml) containing 0.25% Tween 80. The size and size distribution ofthe particles were analyzed by Coulter Counter and light microscopy. Themean diameter by volume was 2 microns.

Particle Preparation 4

A 3% solution of human serum albumin (HSA) in distilled water wasprepared (150 ml) and filtered through a membrane filter (0.45 micron).A filtered solution (0.22 micron) of the product of Example 1 (1.2 g) in96% ethanol (30.0 ml) was slowly added to the HSA solution undervigorous stirring. The microparticles formed were centrifuged and washedrepeatedly before reconstitution in sterile phosphate buffered saline(10.7 ml). The size and size distribution of the particles were analyzedby Coulter Counter and light microscopy. The mean diameter by volume was2.5-3.5 microns.

Particle Preparation 5

A 0.4% solution of human serum albumin (HSA) in distilled water wasprepared (60.0 ml) and filtered through a membrane filter (0.45microns). A filtered solution (0.22 micron) of the product of Example 1(0.6 g) in 96% ethanol (15.0 ml) was slowly added to the HSA solutionunder vigorous homogenizing. The microparticles formed were centrifugedand washed repeatedly before reconstitution in sterile phosphatebuffered saline (5.3 ml) containing 0.4% HSA. The size and sizedistribution of the particles were analyzed by Malvern Mastersizer andlight microscopy. The mean diameter by volume was 1.45 microns.

Particle Preparation 6

A solution containing 0.4% human serum albumin (HSA) and 2% propyleneglycol in distilled water was prepared (60.0 ml) and filtered through amembrane filter (0.45 micron). A filtered solution (0.22 micron) of theproduct of Example 1 (0.6 g) in 96% ethanol (15.0 ml) was slowly addedto the HSA/propylene glycol solution under vigorous homogenizing. Themicroparticles formed were centrifuged and washed repeatedly beforereconstitution in sterile phosphate buffered saline (5.3 ml) containing0.2% propylene glycol. The size and size distribution of the particleswere analyzed by Malvern Mastersizer and light microscopy. The meandiameter by volume was 1.5-1.7 microns.

Pharmaceutical Formulation 1

The particles of Particle Preparation 1 (1.0 g) were dispersed in asterile filtered isotonic 0.9% sodium chloride/water for injectionsolution (100 ml) under vigorous stirring until a homogeneous suspensionwas achieved.

Pharmaceutical Formulation 2

The particles of Particle Preparation 1 (1.0 g) were suspended in asterile filtered 0.9% sodium chloride/water for injection solution (100ml) containing bovine serum albumin (3.0 g) under vigorous stirringuntil a homogeneous suspension was achieved.

Pharmaceutical Formulation 3

The particles of Particle Preparation 1 (1.0 g) were suspended in asterile phosphate buffered saline solution (100 ml) until a homogeneoussuspension was achieved.

Pharmaceutical Formulation 4

The particles of Particle Preparation 1 (2.8 g) were suspended in asterile phosphate buffered saline solution (100 ml) until a homogeneoussuspension was achieved.

In Vitro Biodegradation

The powdered product of Example 1 was suspended in Seronorm (0.5 mg/ml)at pH 7.4 and agitated at 37° C. As a control the experiment was alsoperformed in phosphate buffered saline (PBS) at pH 7.4. At differenttime points samples were taken from the supernatant after centrifugationof the vial (4000 rpm, 10 min). The release of Isopaque(5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6triiodobenzenecarboxylic acid) was analysed by HPLC. After 6 hours 100% of thesubstance was hydrolysed. In PBS only 1.1% was hydrolysed during thesame period.

In Vivo Metabolism

The particles of Pharmaceutical Formulation 3 were injectedintravenously into the tail veins of rats. The dose was 200 mg/kg,injection rate 1 ml/min and concentration 10 mg/ml. 15 min afterinjection about 70% of the dose was found in the liver. This uptake gave1.4 mg I/g liver. The iodine content was stable up to 3 hours p.i., andthen decreased to 24% after 6 hours. 24 hours p.i. only 4% was left inthe liver. Bile and urine were sampled during the first 3 hours afterinjection. Excretion through these routes was 8.1 and 3.4% of theinjected dose respectively. All iodine was excreted as Isopaque(5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylicacid). During a 72 hour period all iodine was excreted via the urine orfaeces in equal amounts (about 50% through each). To assess embolizationof particles in the lung capillaries iodine content in this organ wasmeasured. Only 1.3% of the injected dose was found in the lungs 15 minafter injection, and iodine could not be detected in the lungs 24 hourslater. This shows that the pulmonary trapping was minimal.

CT Studies in Rabbit

Contrast enhancement in the liver was investigated in rabbits.Anaesthetized animals were placed in a Siemens CT scanner and injectedwith particles of Pharmaceutical Formulation 4 in the marginal ear vein.Particle concentration was 28 mg/ml. A particle dose corresponding to 75mg I/kg gave an increase in liver contrast from a basal level of 75 HUto about 120 HU. Thus, the contrast enhancement on this dose level wasabout 35-40 HU. This contrast enhancement was stable during theobservation period of 15 minutes. The average iodine content in theselivers was 1.1 mg I/g liver. These results were compared to dynamic CTin other rabbits which were injected with iohexol (350 mg I/ml). About 8times more iodine had to be injected in these animals to achieve thesame contrast enhancement of the liver. With this vascular contrastmedium, the enhancement was transient, lasting for one or two minutes.

We claim:
 1. A compound which is a water-insoluble iodinated ester ofthe formula (I): ##STR3## in which R¹ is a substituted or unsubstitutedC₁₋₂₀ aliphatic, C₇₋₂₀ -araliphatic or C₆₋₂₀ aryl group or a 5 or 6membered heterocyclic group having one or more hetero atoms selectedfrom O, S and N;R² is hydrogen or a substituted or unsubstituted C₁₋₆aliphatic, C₆₋₁₀ aryl or C₇₋₂₀ araliphatic group; and R³ is a group asdefined above for R¹, which may be the same as or different from R¹, orR² and R³ together represent a substituted or unsubstituted C₁₋₄alkylene group, the compound containing at least one iodine atom andbeing metabolisable to products which are soluble in body fluids and arephysiologically acceptable.
 2. An ester as claimed in claim 1 wherein R¹and/or R³ comprises an iodinated phenyl group.
 3. An ester as claimed inclaim 1 wherein R¹ and/or R³ comprises a triiodophenyl group.
 4. Aninjectable contrast medium composition comprising a compound of formula(I) as claimed in claim 1 in particulate form, in suspension in a liquidfor injection.
 5. A composition as claimed in claim 4 wherein the meanparticle size is within the range 0.002 to 7 micrometers.